Ca2+-independent PLA2 controls endothelial store-operated Ca2+ entry and vascular tone in intact aorta.
During an agonist stimulation of endothelial cells, the sustained Ca2+ entry occurring through store-operated channels has been shown to significantly contribute to smooth muscle relaxation through the release of relaxing factors such as nitric oxide (NO). However, the mechanisms linking Ca2+ stores depletion to the opening of such channels are still elusive. We have used Ca2+ and tension measurements in intact aortic strips to investigate the role of the Ca2+-independent isoform of phospholipase A2 (iPLA2) in endothelial store-operated Ca2+ entry and endothelium-dependent relaxation of smooth muscle. We provide evidence that iPLA2 is involved in the activation of endothelial store-operated Ca2+ entry when Ca2+ stores are artificially depleted. We also show that the sustained store-operated Ca2+ entry occurring during physiological stimulation of endothelial cells with the circulating hormone ATP is due to iPLA2 activation and significantly contributes to the amplitude and duration of ATP-induced endothelium-dependent relaxation. Consistently, both iPLA2 metabolites arachidonic acid and lysophosphatidylcholine were found to stimulate Ca2+ entry in native endothelial cells. However, only the latter triggered endothelium-dependent relaxation through NO release, suggesting that lysophosphatidylcholine produced by iPLA2 upon Ca2+ stores depletion may act as an intracellular messenger that stimulates store-operated Ca2+ entry and subsequent NO production in endothelial cells. Finally, we found that ACh-induced endothelium relaxation also depends on iPLA2 activation, suggesting that the iPLA2-dependent control of endothelial store-operated Ca2+ entry is a key physiological mechanism regulating arterial tone.
Boittin
François-Xavier
FX
Department of Zoology and Animal Biology, Laboratory of Vascular Cell Physiology, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland. Francois.Boittin@zoo.unige.ch
Gribi
Françoise
F
Serir
Karima
K
Bény
Jean-Louis
JL
D000109:Acetylcholine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology*; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054522:Group VI Phospholipases A2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006834:Hydrazines / Q000494:pharmacology; D008244:Lysophosphatidylcholines / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D001095:Arachidonic Acids; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D006834:Hydrazines; D008244:Lysophosphatidylcholines; D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; C081565:arachidonyltrifluoromethane; D016718:Arachidonic Acid; D009569:Nitric Oxide; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D000255:Adenosine Triphosphate; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D000109:Acetylcholine